This application is a resubmission in response to PA-10-069, entitled "Exploratory Developmental Research Grant Program." Methamphetamine (METH) dependence has profound adverse medical, social and societal consequences. A paucity of studies has examined potential medications for treating this disorder, including the efficacy of medications to alleviate METH withdrawal symptoms. Medications development has also been hampered by generally employing study designs that examine the initiation of abstinence, rather preventing relapse. Recent evidence suggests that norepinephrine plays a more important role in the addiction process than previously thought, particularly in relapse as well as the expression of psychostimulant withdrawal. A promising therapeutic approach involves the use of indirect agonist pharmacotherapy for METH dependence;however, there are a limited number of studies and considerable variability in methodology. Despite successful agonist treatments for dependence on other drugs, there has been a reluctance to examine more closely agonist treatment for stimulant dependence for several reasons. Thus, given that recent evidence suggests agents that alter noradrenergic activity may be effective in treating drug dependence, this application will examine the efficacy of the selective noradrenergic reuptake inhibiter atomoxetine in 1) delaying time to relapse and 2) alleviating withdrawal symptoms in recently abstinent METH-dependent individuals. This 11-wk, randomized, double blind, placebo-controlled clinical trial will provide treatment for 40 METH-dependent (18-65 yrs) individuals over a two-year period. Participants first will reside at a residential facility (Recovery Centers of Arkansas) to initiate initial drug abstinence and be inducted on the study medication. They will be randomized by sex, severity of dependence and childhood diagnosis of ADHD to receive either placebo (N=20) or atomoxetine (80 mg/day;N=20). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 3-10. During the outpatient portion of the trial, subjects participate in weekly individual cognitive behavioral therapy. During the trial, participants are given monetary incentives for complying with study requirements. At the end of 10 weeks, patients will be taken off the study medication, monitored during week 11, and referred to an appropriate treatment program. Efficacy will be determined by length of time in treatment, alleviation of withdrawal symptoms, length of time to lapse/relapse as determined by urine toxicology, and psychosocial functioning. The findings of this trial, if positive, will support an R01 application to examine the efficacy of atomoxetine and prognostic relevance of various factors in a larger sample. As such, these findings may shift clinical practice with the development of an efficacious pharmacotherapy for METH dependence. PUBLIC HEALTH RELEVANCE: Methamphetamine dependence is a serious public health problem, with methamphetamine abusers being at risk for significant morbidity and mortality, including HIV. To date, no medication or psychotherapeutic strategy has shown robust, long-term efficacy in treating this disorder. This clinical trial will examine whether atomoxetine shows promise in alleviating withdrawal symptoms and preventing relapse relative to placebo in recently abstinent methamphetamine-dependent individuals. Findings of this study will not only shed light on whether atomoxetine may improve upon treatment for this disorder but also inform future medication development strategies for improving treatment for drug dependence disorders. Discovering efficacious minimal risk interventions that show more robust, longer-term outcomes would be beneficial both to the individual and society.